Lack of information on mechanisms of protection against HIV/SIV infection remains one of the leading obstacles to the development of a safe and effective AIDS vaccine. Vaccination of macaques with attenuated SIV strains has consistently proved to be the most effective means of inducing protection against pathogenic SIV challenge and offers the best available experimental model to define specific mechanisms responsible for protection. Previous studies from our group have provided evidence that SIV-specific CD8+ T cell and humoral responses both contribute to protective immunity induced by SIVAnef but have not been able to assess their relative importance or the potential contributions of novel adaptive (eg CD4+ T effector cells) or innate immune responses to protection. The goal of the current proposal is to utilize a number of novel techniques to carry out a comprehensive analysis of the role of adaptive and innate immune responses in mediating protection induced by SIVAnef against vaginal challenge, one of the most important modes of HIV transmission. Specific aims include: 1: To examine the evolution of adaptive and innate immune responses induced by SIVAnef and to correlate these responses with protection against homologous and heterologous challenge. 2: To examine the effect of prolonged B cell depletion on protective immunity induced by SIVANef. 3: To examine viral replication, innate and adaptive immune responses in the female reproductive tract of SIVAnef-vaccinated animals after vaginal challenge.